Carbon monoxide releasing rhenium compounds for medical use

Abstract

The present invention relates to new rhenium compounds of formula (I) with medical utility, corresponding pharmaceutical compositions as well as medical uses thereof.

1 . A method for the prophylaxis and/or treatment of diseases and/or medical condition involving hypoxic, anoxic and/or mammalian inflamed tissue, the method comprising the administration to a mammal in need thereof or the ex-vivo administration to a tissue before grafting into a mammal in need thereof of a therapeutically effective amount of at least one compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein Re is Re(I) or Re(II); n is selected from 2 − , 1 − , 0, 1 +  and 2 + ; L 1 , L 2 , L 3  and L 4  are pharmaceutically acceptable monodentate ligands comprising either at least one heteroatom or at least one carbon-carbon double or triple bond for binding the rhenium metal of the complex; or a tautomer, an isomeric form, a racemate, a single enantiomer, a diastereomer or mixtures thereof, pharmaceutically acceptable salt thereof, prodrug thereof or an effective amount of a pharmaceutical composition thereof. 
       
     
     
         2 . The method according to  claim 1 , wherein the disease and/or medical condition is selected from the group consisting of cardiovascular diseases, ischemia-reperfusion injury, inflammatory diseases, traumatic injury, transplant rejection, platelet aggregation and/or monocyte activation; neuron degeneration of the nervous system, radiation damage, cancer, penile erectile dysfunction, adult respiratory distress syndrome, and disorders of the circadian rhythm. 
     
     
         3 . The method according to  claim 1 , wherein the cardiovascular disease is selected from cardiac hypoxia, cardiac infarction, cardiac hypertrophy, arteriosclerosis and hypertension. 
     
     
         4 . The method according to  claim 1 , wherein the inflammatory disease is selected from asthma and angina. 
     
     
         5 . The method according to  claim 1 , wherein the traumatic injury is selected from a brain, kidney or liver injury. 
     
     
         6 . The method according to  claim 2 , wherein the disease and/or medical condition is ischemia-reperfusion injury. 
     
     
         7 . The method according to  claim 1 , wherein the monodentate ligands comprise a heteroatom selected from N, O, S and P. 
     
     
         8 . The method according to  claim 1 , wherein the compound of Formula (I) wherein Re is Re (II). 
     
     
         9 . The method according to  claim 1 , wherein the compound of Formula (I) wherein at least one of L 1 , L 2 , L 3  and L 4  is independently selected from the group consisting of alkyl and cycloalkyl comprising at least one heteroatom, alkenyl, alkynyl, alkylidene, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxyl, oxo, halogen, trifluoromethyl, nitro, nitrile, isocyanide, alcohol, phosphine, phosphite, phosphonite, sulphide, sulfoxide and amino or guanidine, each amino or guanidine optionally mono-, di- or tri-substituted by alkyl, acyl or alkoxycarbonyl, each member of the group optionally substituted by one to four R″; wherein each R″ is independently selected from alkyl, alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted by alkyl, acyl or alkoxycarbonyl, wherein any members of the group and/or R″ are optionally halogenated where possible. 
     
     
         10 . The method according to  claim 1 , wherein the compound of Formula (I) is of formula [Re II Br 2 (CO) 2 (L) 2 ] wherein at least at least one L is selected from the group consisting of halides, carbon monoxide, N-methyl imidazole, benzimidazole, 4-methyl pyridine, imidazole, pyridine, C 1-6  alkyl cyanide, and alcohol, optionally substituted by one to four R″ where possible; wherein each R″ is independently selected from the group consisting of alkyl, alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted by C 1-6  alkyl, C 1-6  acyl or C 2-7  alkoxycarbonyl; wherein any members of the group and/or of the R″ are optionally halogenated where possible. 
     
     
         11 . The method according to  claim 1 , wherein the compound of Formula (I) is such that at least one of L 1 , L 2 , L 3  and L 4  is Vitamin B12 optionally substituted optionally substituted by one to four R″ where possible; wherein each R″ is independently selected from alkyl, alkenyl, alkynyl, alkylidene, cycloalkyl, aryl, heteroaryl, arylalkyl, aryloxy, alkoxy, alkylthio, acyl, alkoxycarbonyl, acyloxy, acylamino, sulphonylamino, aminosulfonyl, alkylsulfonyl, carboxy, carboxamide, hydroxy, halogen, trifluoromethyl, nitro, nitrile and amino optionally mono-, di- or tri-substituted by C 1-6  alkyl, C 1-6  acyl or C 2-7  alkoxycarbonyl; wherein any of the R″ are optionally halogenated where possible. 
     
     
         12 . The method according to  claim 1 , wherein the compound of Formula (I) is selected from the following group: [Re(CO) 2 (Br) 4 ] 2− , [Re II (CO) 2 Br 2 (N-methylimidazole) 2 ], [Re II (CO) 2 Br 2 (benzimidazole) 2 ], [Re II (CO) 2 Br 2 (4-methyl picoline) 2 ], [Re II (CO) 2 Br 2 (Imidazole) 2 ], [Re II (CO) 2 Br 2 (pyridine) 2 ] and [Et 4 N][Re(CO) 2 Br 2 (4-picoline amine) 2 ]. 
     
     
         13 . The method according to  claim 1 , wherein the compound of Formula (I) is selected from the following group: (Et 4 N) 2 [Re 2 Br 6 (CO) 4 (pyrazine)], (Et 4 N) 2 [Re 2 Br 6 (CO) 4 (pyrimidine)] and (Et 4 N) 2 [Re 2 Br 6 (CO) 4 (5-Br-pyrimidine)]. 
     
     
         14 . The method according to  claim 11 , wherein the compound of Formula (I) is selected from the following group: 
       
         
           
           
               
               
           
         
       
     
     
         15 . The method according to  claim 1 , wherein the ligands L1-4 are in a cis-trans-cis stereochemistry. 
     
     
         16 . The method according to  claim 1 , wherein the compound of Formula (I) or a tautomer, an isomeric form, a racemate, a single enantiomer, a diastereomer or mixtures thereof, pharmaceutically acceptable salt thereof, prodrug thereof or an effective amount of a pharmaceutical composition thereof is administered ex-vivo in a vein graft before grafting.